Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Abstract

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

“…These data, combined with the finding that more selective AAK1 and GAK inhibitors lacking affinity to most of sunitinib's and erlotinib's cancer targets (e.g., VEGFR and EGFR) (28,35) have anti-DENV activity, indicate that AAK1 and GAK are important mediators of the observed antiviral effect. Nevertheless, these data cannot rule out additional potential cellular targets mediating the anti-DENV activity of these compounds.…”

Splicing variation of BMP2K balances endocytosis, COPII trafficking and autophagy in erythroid cells

“…A growing body of evidence suggests that AAK1 and BMP2K serine-threonine kinases might be of high importance for human physiology, with AAK1 implicated in functioning of the central nervous system (Kostich et al, 2016;Ultanir et al, 2012) and BMP2K involved in leukemogenesis (Hirabayashi et al, 2017;Pandzic et al, 2016;Wang et al, 2020). Although AAK1 is an established regulator of CME (Agajanian et al, 2019;Loi et al, 2016;Ricotta et al, 2002;Sorensen & Conner, 2008), the cellular functions of BMP2K are largely unknown.…”

The role of P2Y6 receptors in the maintenance of neuropathic pain and its improvement of oxidative stress in rats

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